Abstract
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.